Abstract: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer type in the world, and there has been only a limited increase in survival rate over the last 30 years unlike the significant survival improvements in better-studied cancer types such as breast and prostate. Although molecular alterations are overall poorly characterized in HNSCC, the actin-binding protein cortactin has been shown to be overexpressed in 30-40% of HNSCC, due to the presence of its gene (CTTN) in the 11q13 amplicon. Importantly, numerous studies have shown that cortactin overexpression at the protein, mRNA and genomic DNA levels is highly correlated with poor prognosis. Cortactin was originally identified as a src kinase substrate, and has been shown to be important in actin cytoskeleton rearrangement, migration, and invasion. Our laboratory has shown cortactin to be important for various cancer-associated phenotypes in HNSCC, including tumor growth and invasion, serum- and anchorage-independent growth, migration and invadopodia formation. Our recent data suggest that underlying mechanisms for these phenotypes include alterations in membrane trafficking, with consequent regulation in secretion of proteinases and other autocrine secreted factors. Cortactin binds to a number of proteins necessary for cancer progression, including Src kinase and filamentous actin (F-actin). However, the molecular mechanisms and cortactin-binding proteins that are important for these functions of cortactin have yet to be elucidated. To determine the molecular interactions of cortactin that are important in promoting tumor aggression, I propose two specific aims: 1, to determine which cortactin binding interactions are critical for cortactin-dependent HNSCC cell phenotypes in vitro and in vivo; and 2, to test the role of cortactin binding partners in cortactin-sensitive cellular phenotypes. By investigating these aims, I hope to identify new potential therapeutic targets for treatment of HNSCC.